Radiotherapy and chemotherapy are well-established treatment methods for malignant diseases. Cells, which grow and divide rapidly, are most vulnerable to the effects of radiation and cytotoxic agents. Among those effected are tumor cells, and normal cells including hair and intestinal cells, and cells of the hemopoietic and immune systems. Damage to normal cells of the hemopoietic and immune systems by radiation and cytotoxic agents often has life-threatening consequences, and it limits the ability to administer a full therapeutic dose.
There has been extensive research to identify agents which will protect normal hemopoietic and immunologic cells from the effects of radiotherapy and chemotherapy, or aid in the reconstitution of cells suppressed by these therapies. For example, transforming growth factor beta-1 has been reported to be useful for protecting hematopoietic stem cells from the myelotoxicity of chemotherapeutic drugs or radiation therapy (U.S. Pat. No. 5,278,145 to Keller et al.). A lyophilized composition containing human albumin in thymosin alpha 1 was also reported to exert a preventative activity against progression of leukemia in mice whose immune systems were severely damaged by treatment with cytostatic agents or radiation treatment. Hemopoietic growth factors such as interleukin-3 and CSF have been used to potentiate immune response or assist in reconstituting normal blood following radiation-or-chemotherapy-induced hematopoietic cell suppression (WO 88/05469 to Anderson et al., U.S. Pat. No. 4,959,455 to Ciarletta et al; U.S. Pat. No. 4,999,291 to Souza).
Semina et al. (Radiatsionnaya Biologiya Radioekologiya 33(3), 1993; WO 89/06134) have shown that the levorotary (L) enantiomer of the dipeptide H-Glu-Trp-OH acts as an immunostimulant and can induce the proliferation of cells. As such, these dipeptides are useful in reconstituting hemopoietic and immune cells after chemotherapy or irradiation therapy.
Several peptides with immunoregulatory properties have been synthesized (for example, SU 1,582,393; EP 230,052; U.S. Pat. Nos. 4,190,646; 5,008,246; and 5,013,723). Many scientific laboratories have tried to develop methods for preparing synthetic derivatives of natural peptides, which are more active than their natural analogs (for example, EP 136,720; and EP 137,904).
Australian Patent No. AU-B-29308/89 (corresponding to WO 089/06134) teaches the preparation of Glu-Trp and its use for treating immune deficiency conditions. WO 93/08815 issued to Khavinson et al. discloses the peptide Glu-Trp and cyclic monomers and polymers thereof, for use in the treatment of immunosuppression.
Deigin et al., U.S. Pat. No. 6,051,683, issued Apr. 18, 2000 and U.S. Pat. No. 6,159,940 issued Dec. 12, 2002, describe immunoregulatory peptides of the general formula:X-Glu-Trp-Ythat can stimulate the immune response and modulate hemopoiesis;    wherein X is hydrogen, glycine, alanine, leucine, isoleucine, valine, N-valine, proline, tyrosine, phenylalanine, tryptophan, D-alanine, D-leucine, D-isoleucine, D-valine, D-N-valine, D-proline, D-tyrosine, D-phenylalanine, D-tryptophan, γ-aminobutyric acid or ξ-aminocaproic acid; Y is glycine, alanine, leucine, isoleucine, valine, N-valine, proline, tyrosine, phenylalanine, tryptophan, D-alanine, D-leucine, D-isoleucine, D-valine, D-N-valine, D-proline, D-tyrosine, D-phenylalanine, D-tryptophan, γ-aminobutyric acid, ξ-aminocaproic acid, —OH, NH2, N2H3, or a mono- or di-substituted amide (C1-C3); and more particularly H-He-Glu-Trp-OH.
Deign et al., U.S. Pat. No. 5,736,519 issued Apr. 7, 1998; U.S. Pat. No. 6,103,699 issued Aug. 15, 2000 and U.S. Pat. No. 6,410,515 issued Jun. 25, 2003 describe immunoregulatory peptides of the general formula:X-A-D-Trp-Yfor reconstitution of cells after radiation or chemotherapy, for inhibiting cell proliferation, and for immunosuppression, wherein X is hydrogen, glycine, alanine, leucine, isoleucine, valine, N-valine, proline, tyrosine, phenylalanine, tryptophan, D-alanine, D-leucine, D-isoleucine, D-valine, D-N-valine, D-proline, D-tyrosine, D-phenylalanine, D-tryptophan, γ-aminobutyric acid or ξ-aminocaproic acid; A is D-glutamic acid or D-γ-glutamic acid; and Y is glycine, alanine, leucine, isoleucine, valine, N-valine, proline, tyrosine, phenylalanine, tryptophan, D-alanine, D-leucine, D-isoleucine, D-valine, D-N-valine, D-proline, D-tyrosine, D-phenylalanine, D-tryptophn, γ-aminobutyric acid, ξ-aminocaproic acid, hydroxyl, or an amide group; and more particularly H-γ-DGlu-Trp-OH.
Deigin et al., U.S. Pat. No. 6,184,208, issued Feb. 6, 2001 and U.S. Pat. No. 6,248,716, issued Jun. 19, 2001 describe immunoregulatory peptides of the general formula:X-Tyr-Y-Phe-Z-Athat reduce stress, stimulate weight gain, epithelium growth zone, wound healing and reparative and anabolic processes; wherein X is hydrogen, arginine, D-arginine, ornithine, D-ornithine, lysine, D-lysine, homoarginine, D-homoarginine, citrulline, D-citrulline; Tyr is tyrosine; Y is D-alanine, D-valine, D-leucine, D-isoleucine, D-phenylalanine, D-asparagine, D-tryptophan, D-proline, D-serine, D-threonine, D-tyrosine, D-hydroxyproline, D-cysteine, D-cysteyl-cysteine, D-methionine, D-lysine, D-homoarginine, D-arginine, D-histidine, D-aspartic acid, D-glutamic acid, D-β-alanine, or D-ornithine; Phe is phenylalanine; Z is alanine, D-alanine, valine, D-valine, leucine, D-leucine, isoleucine, D-isoleucine, phenylalanine, D-phenylalanine, asparagine, D-asparagine, glycine, glutamine, D-glutamine, tryptophan, D-tryptophan, proline, D-proline, serine, D-serine, threonine, D-threonine, tyrosine, D-tyrosine, hydroxyproline, D-hydroxyproline, cysteine, D-cysteine, cysteyl-cysteine, cysteine-D-cysteine, D-cysteyl cysteine, D-cysteine-D-cysteine, methionine, D-methionine, lysine, D-lysine, arginine, D-arginine, histidine, D-histidine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, β-alanine, D-β-alanine, ornithine, or D-ornithine; and, A is hydroxyl or substituted amide (C1-C3); and more particularly H-Arg-Tyr-D-Ala-Phe-Gly-OH.
Compositions for the delivery, in particular, oral delivery, of active agents comprising a diketopiperazine-based system are described in several patents and patent applications owned by Emisphere Technologies, Inc., including for example, U.S. Pat. Nos. 6,663,898, 6,395,774, 6,331,318, 5,976,569 and 5,693,338, as well as U.S. Patent Application Nos. 20030198658, 20030155993 and 20030028250. In these compositions, the diketopiperazine is typically added as a separate component.
There remains a need for effective methods for delivering bioactive compounds to the body that may be readily tailored for any applications or for multiple applications.